Amino Acids

, Volume 42, Issue 2–3, pp 597–610 | Cite as

A combined model of hepatic polyamine and sulfur amino acid metabolism to analyze S-adenosyl methionine availability

  • Armando Reyes-Palomares
  • Raúl Montañez
  • Francisca Sánchez-Jiménez
  • Miguel Ángel Medina
Original Article


Many molecular details remain to be uncovered concerning the regulation of polyamine metabolism. A previous model of mammalian polyamine metabolism showed that S-adenosyl methionine availability could play a key role in polyamine homeostasis. To get a deeper insight in this prediction, we have built a combined model by integration of the previously published polyamine model and one-carbon and glutathione metabolism model, published by different research groups. The combined model is robust and it is able to achieve physiological steady-state values, as well as to reproduce the predictions of the individual models. Furthermore, a transition between two versions of our model with new regulatory factors added properly simulates the switch in methionine adenosyl transferase isozymes occurring when the liver enters in proliferative conditions. The combined model is useful to support the previous prediction on the role of S-adenosyl methionine availability in polyamine homeostasis. Furthermore, it could be easily adapted to get deeper insights on the connections of polyamines with energy metabolism.


Metabolic modeling Systems biology Polyamines S-adenosyl methionine Methionine cycle Folate cycle 



Our experimental work is supported by grants PS09/02216, SAF2008-02522 and SAF2011-26518 (Spanish Ministry of Science and Innovation), and PIE P08-CTS-3759, CVI-6585 and funds from group BIO-267 (Andalusian Government). The “CIBER de Enfermedades Raras” is an initiative from the ISCIII (Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ARP is the recipient of a FPU Fellowship (Spanish Ministry of Education).

Conflict of interest

The authors have declared no conflict of interest.

Supplementary material

726_2011_1035_MOESM1_ESM.xml (328 kb)
Supplementary material 1 (XML 328 kb)
726_2011_1035_MOESM2_ESM.xml (333 kb)
Supplementary material 2 (XML 333 kb)
726_2011_1035_MOESM3_ESM.pdf (2.8 mb)
Supplementary material 3 (PDF 2884 kb)
726_2011_1035_MOESM4_ESM.pdf (219 kb)
Supplementary material 4 (PDF 218 kb)
726_2011_1035_MOESM5_ESM.xlsx (143 kb)
Supplementary material 5 (XLSX 142 kb)
726_2011_1035_MOESM6_ESM.pdf (69 kb)
Supplementary material 4 (PDF 68.6 kb)


  1. Agostinelli E, Arancia G, Vedova LD, Belli F, Marra M, Salvi M, Toninello A (2004) The biological functions of polyamine oxidation products by amine oxidases: perspectives of clinical applications. Amino Acids 27:347–358PubMedCrossRefGoogle Scholar
  2. Agostinelli E, Marques MPM, Calheiros R, Gil FPSC, Tempera G, Viceconte N, Battaglia V, Grancara S, Toninello A (2010) Polyamines: fundamental characters in chemistry and biology. Amino Acids 38:393–403PubMedCrossRefGoogle Scholar
  3. Andrianantoandro E, Basu S, Karig DK, Weiss R (2006) Synthetic biology: new engineering rules for an emerging discipline. Mol Syst Biol 2:2006.0028Google Scholar
  4. Auvinen M, Paasinen A, Andersson LC, Hölttä E (1992) Ornithine decarboxylase activity is critical for cell transformation. Nature 360:355–358PubMedCrossRefGoogle Scholar
  5. Berntsson PS, Alm K, Oredsson SM (1999) Half-lives of ornithine decarboxylase and S-adenosylmethionine decarboxylase activities during the cell cycle of Chinese hamster ovary cells. Biochem Biophys Res Commun 263:13–16PubMedCrossRefGoogle Scholar
  6. Cai J, Mao Z, Hwang JJ, Lu SC (1998) Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer Res 58:1444–1450PubMedGoogle Scholar
  7. Chandrasekaran S, Price ND (2010) Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis. Proc Natl Acad Sci USA 107:17845–17850PubMedCrossRefGoogle Scholar
  8. Chaves P, Correa-Fiz F, Melgarejo E, Urdiales JL, Medina MA, Sánchez-Jiménez F (2007) Development of an expression macroarray for amine metabolism-related genes. Amino Acids 33:519–523CrossRefGoogle Scholar
  9. Corrales FJ, Pérez-Mato I, Sánchez del Pino MM, Ruiz F, Castro C, García-Trevijano ER, Latasa U, Martínez-Chantar ML, Martínez-Cruz A, Avila MA, Mato JM (2002) Regulation of mammalian liver methionine adenosyltransferase. J Nutr 132:2377S–2381SPubMedGoogle Scholar
  10. Curien G, Bastien O, Robert-Genthon M, Cornish-Bowden A, Cárdenas ML, Dumas R (2009) Understanding the regulation of aspartate metabolism using a model based on measured kinetic parameters. Mol Syst Biol 5:271PubMedCrossRefGoogle Scholar
  11. Duarte NC, Becker SA, Jamshidi N, Thiele I, Mo ML, Vo TD, Srivas R, Palsson BØ (2007) Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci USA 104:1777–1782PubMedCrossRefGoogle Scholar
  12. Finkelstein JD, Martin JJ (1984) Inactivation of betaine-homocysteine methyltransferase by adenosylmethionine and adenosylethionine. Biochem Biophys Res Commun 118:14–19PubMedCrossRefGoogle Scholar
  13. Finkelstein JD, Kyle WE, Martin JL, Pick AM (1975) Activation of cystathionine synthase by adenosylmethionine and adenosylethionine. Biochem Biophys Res Commun 66:81–87PubMedCrossRefGoogle Scholar
  14. Gil B, Casado M, Pajares MA, Boscá L, Mato JM, Martín-Sanz P, Alvarez L (1996) Differential expression pattern of S-adenosylmethionine synthetase isoenzymes during rat liver development. Hepatology 24:876–881PubMedGoogle Scholar
  15. Grillo MA, Colombatto S (2008) S-adenosylmethionine and its products. Amino Acids 34:187–193PubMedCrossRefGoogle Scholar
  16. Hartwell LH, Hopfield JJ, Leibler S, Murray AW (1999) From molecular to modular cell biology. Nature 402:C47–C52PubMedCrossRefGoogle Scholar
  17. Holme P (2011) Metabolic robustness and network modularity: a model study. PLoS ONE 6:e16605PubMedCrossRefGoogle Scholar
  18. Huang ZZ, Mao Z, Cai J, Lu SC (1998) Changes in methionine adenosyltransferase during liver regeneration in the rat. Am J Physiol 275:G14–G21PubMedGoogle Scholar
  19. Huang ZZ, Chen C, Zeng Z, Yang H, Oh J, Chen L, Lu SC (2001) Mechanism and significance of increased glutathione level in human hepatocellular carcinoma and liver regeneration. FASEB J 15:19–21PubMedGoogle Scholar
  20. Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, Arkin AP, Bornstein BJ, Bray D, Cornish-Bowden A, Cuellar AA, Dronov S, Gilles ED, Ginkel M, Gor V, Goryanin II, Hedley WJ, Hodgman TC, Hofmeyr J-H, Hunter PJ, Juty NS, Kasberger JL, Kremling A, Kummer U, Le Novère N, Loew LM, Lucio D, Mendes P, Minch E, Mjolsness ED, Nakayama Y, Nelson MR, Nielsen PF, Sakurada T, Schaff JC, Shapiro BE, Shimizu TS, Spence HD, Stelling J, Takahashi K, Tomita M, Wagner J, Wang J, Forum S (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19:524–531PubMedCrossRefGoogle Scholar
  21. Jamshidi N, Palsson BØ (2008) Formulating genome-scale kinetic models in the post-genome era. Mol Syst Biol 4:171PubMedCrossRefGoogle Scholar
  22. Jell J, Merali S, Hensen ML, Mazurchuk R, Spernyak JA, Diegelman P, Kisiel ND, Barrero C, Deeb KK, Alhonen L, Patel MS, Porter CW (2007) Genetically altered expression of spermidine/spermine N1-acetyltransferase affects fat metabolism in mice via acetyl-CoA. J Biol Chem 282:8404–8413PubMedCrossRefGoogle Scholar
  23. Kee K, Foster BA, Merali S, Kramer DL, Hensen ML, Diegelman P, Kisiel N, Vujcic S, Mazurchuk RV, Porter CW (2004) Activated polyamine catabolism depletes acetyl-CoA pools and suppresses prostate tumor growth in TRAMP mice. J Biol Chem 279:40076–40083PubMedCrossRefGoogle Scholar
  24. Korendyaseva TK, Kuvatov DN, Volkov VA, Martinov MV, Vitvitsky VM, Banerjee R, Ataullakhanov FI (2008) An allosteric mechanism for switching between parallel tracks in mammalian sulfur metabolism. PLoS Comput Biol 4:e1000076PubMedCrossRefGoogle Scholar
  25. Korhonen VP, Niiranen K, Halmekytö M, Pietilä M, Diegelman P, Parkkinen JJ, Eloranta T, Porter CW, Alhonen L, Jänne J (2001) Spermine deficiency resulting from targeted disruption of the spermine synthase gene in embryonic stem cells leads to enhanced sensitivity to antiproliferative drugs. Mol Pharmacol 59:231–238PubMedGoogle Scholar
  26. Kotb M, Mudd SH, Mato JM, Geller AM, Kredich NM, Chou JY, Cantoni GL (1997) Consensus nomenclature for the mammalian methionine adenosyltransferase genes and gene products. Trends Genet 13:51–52PubMedCrossRefGoogle Scholar
  27. Kramer DL, Sufrin JR, Porter CW (1987) Relative effects of S-adenosylmethionine depletion on nucleic acid methylation and polyamine biosynthesis. Biochem J 247:259–265PubMedGoogle Scholar
  28. Kramer DL, Sufrin JR, Porter CW (1988) Modulation of polyamine-biosynthetic activity by S-adenosylmethionine depletion. Biochem J 249:581–586PubMedGoogle Scholar
  29. Kramer DL, Diegelman P, Jell J, Vujcic S, Merali S, Porter CW (2008) Polyamine acetylation modulates polyamine metabolic flux, a prelude to broader metabolic consequences. J Biol Chem 283:4241–4251PubMedCrossRefGoogle Scholar
  30. Kubo S, Tamori A, Nishiguchi S, Kinoshita H, Hirohashi K, Kuroki T, Omura T, Otani S (1998) Effect of alcohol abuse on polyamine metabolism in hepatocellular carcinoma and noncancerous hepatic tissue. Surgery 123:205–211PubMedCrossRefGoogle Scholar
  31. Latasa MU, Boukaba A, García-Trevijano ER, Torres L, Rodríguez JL, Caballería J, Lu SC, López-Rodas G, Franco L, Mato JM, Avila MA (2001) Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: role in liver regeneration. FASEB J 15:1248–1250PubMedGoogle Scholar
  32. Lauffenburger DA (2000) Cell signaling pathways as control modules: complexity for simplicity? Proc Natl Acad Sci USA 97:5031–5033PubMedCrossRefGoogle Scholar
  33. Le Novère N, Hucka M, Mi H, Moodie S, Schreiber F, Sorokin A, Demir E, Wegner K, Aladjem MI, Wimalaratne SM, Bergman FT, Gauges R, Ghazal P, Kawaji H, Li L, Matsuoka Y, Villéger A, Boyd SE, Calzone L, Courtot M, Dogrusoz U, Freeman TC, Funahashi A, Ghosh S, Jouraku A, Kim S, Kolpakov F, Luna A, Sahle S, Schmidt E, Watterson S, Wu G, Goryanin I, Kell DB, Sander C, Sauro H, Snoep JL, Kohn K, Kitano H (2009) The systems biology graphical notation. Nat Biotechnol 27:735–741PubMedCrossRefGoogle Scholar
  34. Li C, Courtot M, Le Novère N, Laibe C (2010) Web Services, a free and integrated toolkit for computational modelling software. Briefings Bioinform 11:270–277CrossRefGoogle Scholar
  35. Lu SC (2000) S-Adenosylmethionine. Int J Biochem Cell Biol 32:391–395PubMedCrossRefGoogle Scholar
  36. Ma H, Sorokin A, Mazein A, Selkov A, Selkov E, Demin O, Goryanin I (2007) The Edinburgh human metabolic network reconstruction and its functional analysis. Mol Syst Biol 3:135PubMedCrossRefGoogle Scholar
  37. Marques MPM, Gil FPSC, Calheiros R, Battaglia V, Brunati AM, Agostinelli E, Toninello A (2008) Biological activity of antitumoural MGBG: the structural variable. Amino Acids 34:555–564PubMedCrossRefGoogle Scholar
  38. Martínez-Chantar ML, García-Trevijano ER, Latasa MU, Pérez-Mato I, Sánchez del Pino MM, Corrales FJ, Avila MA, Mato JM (2002) Importance of a deficiency in S-adenosyl-l-methionine synthesis in the pathogenesis of liver injury. Am J Clin Nutr 76:1177S–1182SPubMedGoogle Scholar
  39. Martínez-Chantar ML, Latasa MU, Varela-Rey M, Lu SC, García-Trevijano ER, Mato JM, Avila MA (2003) l-methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells: role of S-adenosylmethionine. J Biol Chem 278:19885–19890PubMedCrossRefGoogle Scholar
  40. Martinov MV, Vitvitsky VM, Mosharov EV, Banerjee R, Ataullakhanov FI (2000) A substrate switch: a new mode of regulation in the methionine metabolic pathway. J Theor Biol 204:521–532PubMedCrossRefGoogle Scholar
  41. Martinov MV, Vitvitsky VM, Banerjee R, Ataullakhanov FI (2010) The logic of the hepatic methionine metabolic cycle. Biochim Biophys Acta 1804:89–96PubMedGoogle Scholar
  42. Mato JM, Corrales FJ, Lu SC, Avila MA (2002) S-Adenosylmethionine: a control switch that regulates liver function. FASEB J 16:15–26PubMedCrossRefGoogle Scholar
  43. Medina MA, Urdiales JL, Rodríguez-Caso C, Ramírez FJ, Sánchez-Jiménez F (2003) Biogenic amines and polyamines: similar biochemistry for different physiological missions and biomedical applications. Crit Rev Biochem Mol Biol 38:23–59PubMedCrossRefGoogle Scholar
  44. Medina MA, Correa-Fiz F, Rodríguez-Caso C, Sánchez-Jiménez F (2005) A comprehensive view of polyamine and histamine metabolism to the light of new technologies. J Cell Mol Med 9:854–864PubMedCrossRefGoogle Scholar
  45. Melgarejo E, Urdiales JL, Sánchez-Jiménez F, Medina MA (2010) Targeting polyamines and biogenic amines by green tea epigallocatechin-3-gallate. Amino Acids 38:519–523PubMedCrossRefGoogle Scholar
  46. Mendes P, Hoops S, Sahle S, Gauges R, Dada J, Kummer U (2009) Computational modeling of biochemical networks using COPASI. Methods Mol Biol 500:17–59PubMedCrossRefGoogle Scholar
  47. Mikol YB, Poirier LA (1981) An inverse correlation between hepatic ornithine decarboxylase and S-adenosylmethionine in rats. Cancer Lett 13:195–201PubMedCrossRefGoogle Scholar
  48. Montañez R, Sánchez-Jiménez F, Aldana-Montes JF, Medina MA (2007) Polyamines: metabolism to systems biology and beyond. Amino Acids 33:283–289PubMedCrossRefGoogle Scholar
  49. Montañez R, Rodríguez-Caso C, Sánchez-Jiménez F, Medina MA (2008) In silico analysis of arginine catabolism as a source of nitric oxide or polyamines in endothelial cells. Amino Acids 34:223–229PubMedCrossRefGoogle Scholar
  50. Montañez R, Medina MA, Solé RV, Rodríguez-Caso C (2010) When metabolism meets topology: reconciling metabolite and reaction networks. Bioessays 32:246–256PubMedCrossRefGoogle Scholar
  51. Newman MEJ (2006) Modularity and community structure in networks. Proc Natl Acad Sci USA 103:8577–8582PubMedCrossRefGoogle Scholar
  52. Nijhout HF, Reed MC, Budu P, Ulrich CM (2004) A mathematical model of the folate cycle: new insights into folate homeostasis. J Biol Chem 279:55008–55016PubMedCrossRefGoogle Scholar
  53. Nijhout HF, Reed MC, Lam S-L, Shane B, Gregory JF, Ulrich CM (2006) In silico experimentation with a model of hepatic mitochondrial folate metabolism. Theor Biol Med Model 3:40PubMedCrossRefGoogle Scholar
  54. Parry L, Balaña Fouce R, Pegg AE (1995) Post-transcriptional regulation of the content of spermidine/spermine N1-acetyltransferase by N1N12-bis(ethyl)spermine. Biochem J 305(Pt 2):451–458PubMedGoogle Scholar
  55. Paz JC, Sánchez-Jiménez F, Medina MA (2001) Characterization of spermine uptake by Ehrlich tumour cells in culture. Amino Acids 21:271–279PubMedCrossRefGoogle Scholar
  56. Pezzato E, Battaglia V, Brunati AM, Agostinelli E, Toninello A (2009) Ca2+ -independent effects of spermine on pyruvate dehydrogenase complex activity in energized rat liver mitochondria incubated in the absence of exogenous Ca2+ and Mg2+. Amino Acids 36:449–456PubMedCrossRefGoogle Scholar
  57. Prudova A, Martinov MV, Vitvitsky VM, Ataullakhanov FI, Banerjee R (2005) Analysis of pathological defects in methionine metabolism using a simple mathematical model. Biochim Biophys Acta 1741:331–338PubMedGoogle Scholar
  58. Prudova A, Bauman Z, Braun A, Vitvitsky VM, Lu SC, Banerjee R (2006) S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. Proc Natl Acad Sci USA 103:6489–6494PubMedCrossRefGoogle Scholar
  59. Raftos JE, Whillier S, Kuchel PW (2010) Glutathione synthesis and turnover in the human erythrocyte: alignment of a model based on detailed enzyme kinetics with experimental data. J Biol Chem 285:23557–23567PubMedCrossRefGoogle Scholar
  60. Rao CV, Arkin AP (2001) Control motifs for intracellular regulatory networks. Annu Rev Biomed Eng 3:391–419PubMedCrossRefGoogle Scholar
  61. Reed MC, Nijhout HF, Sparks R, Ulrich CM (2004) A mathematical model of the methionine cycle. J Theor Biol 226:33–43PubMedCrossRefGoogle Scholar
  62. Reed MC, Thomas RL, Pavisic J, James SJ, Ulrich CM, Nijhout HF (2008) A mathematical model of glutathione metabolism. Theor Biol Med Model 5:8PubMedCrossRefGoogle Scholar
  63. Reyes-Palomares A, Montañez R, Real-Chicharro A, Chniber O, Kerzazi A, Navas-Delgado I, Medina MA, Aldana-Montes JF, Sanchez-Jimenez F (2009) Systems biology metabolic modeling assistant: an ontology-based tool for the integration of metabolic data in kinetic modeling. Bioinformatics 25:834–835PubMedCrossRefGoogle Scholar
  64. Rodríguez-Caso C, Montañez R, Cascante M, Sánchez-Jiménez F, Medina MA (2006) Mathematical modeling of polyamine metabolism in mammals. J Biol Chem 281:21799–21812PubMedCrossRefGoogle Scholar
  65. Russell DH, McVicker TA (1971) Polyamine metabolism in mouse liver after partial hepatectomy. Biochim Biophys Acta 244:85–93PubMedCrossRefGoogle Scholar
  66. Sánchez del Pino MM, Pérez-Mato I, Sanz JM, Mato JM, Corrales FJ (2002) Folding of dimeric methionine adenosyltransferase III: identification of two folding intermediates. J Biol Chem 277:12061–12066PubMedCrossRefGoogle Scholar
  67. Sánchez-Jiménez F, Montañez R, Correa-Fiz F, Chaves P, Rodríguez-Caso C, Urdiales JL, Aldana JF, Medina MA (2007) The usefulness of post-genomics tools for characterization of the amine cross-talk in mammalian cells. Biochem Soc Trans 35:381–385PubMedCrossRefGoogle Scholar
  68. Santamaría E, Muñoz J, Fernandez-Irigoyen J, Sesma L, Mora MI, Berasain C, Lu SC, Mato JM, Prieto J, Avila MA, Corrales FJ (2006) Molecular profiling of hepatocellular carcinoma in mice with a chronic deficiency of hepatic s-adenosylmethionine: relevance in human liver diseases. J Proteome Res 5:944–953PubMedCrossRefGoogle Scholar
  69. Shen-Orr SS, Milo R, Mangan S, Alon U (2002) Network motifs in the transcriptional regulation network of Escherichia coli. Nat Genet 31:64–68PubMedCrossRefGoogle Scholar
  70. Smallbone K, Simeonidis E, Swainston N, Mendes P (2010) Towards a genome-scale kinetic model of cellular metabolism. BMC Syst Biol 4:6PubMedCrossRefGoogle Scholar
  71. Snoep JL, Bruggeman F, Olivier BG, Westerhoff HV (2006) Towards building the silicon cell: a modular approach. BioSystems 83:207–216PubMedCrossRefGoogle Scholar
  72. Stipanuk MH, Dominy JE (2006) Surprising insights that aren’t so surprising in the modeling of sulfur amino acid metabolism. Amino Acids 30:251–256PubMedCrossRefGoogle Scholar
  73. Sullivan DM, Hoffman JL (1983) Fractionation and kinetic properties of rat liver and kidney methionine adenosyltransferase isozymes. Biochemistry 22:1636–1641PubMedCrossRefGoogle Scholar
  74. Vitvitsky V, Mosharov E, Tritt M, Ataullakhanov F, Banerjee R (2003) Redox regulation of homocysteine-dependent glutathione synthesis. Redox Rep 8:57–63PubMedCrossRefGoogle Scholar
  75. Vitvitsky V, Thomas M, Ghorpade A, Gendelman HE, Banerjee R (2006) A functional transsulfuration pathway in the brain links to glutathione homeostasis. J Biol Chem 281:35785–35793PubMedCrossRefGoogle Scholar
  76. Williams-Ashman HG, Coppoc GL, Weber G (1972) Imbalance in ornithine metabolism in hepatomas of different growth rates as expressed in formation of putrescine, spermidine, and spermine. Cancer Res 32:1924–1932PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Armando Reyes-Palomares
    • 1
    • 2
  • Raúl Montañez
    • 1
    • 3
  • Francisca Sánchez-Jiménez
    • 1
    • 2
  • Miguel Ángel Medina
    • 1
    • 2
  1. 1.Department of Molecular Biology and Biochemistry, Faculty of ScienceUniversity of MálagaMálagaSpain
  2. 2.Unit 741, CIBER de Enfermedades Raras (CIBERER), ISCIIIMálagaSpain
  3. 3.Institut de Biologia Evolutiva (CSIC-UPF)BarcelonaSpain

Personalised recommendations